Remdesivir treatment methods

ABSTRACT

Provided herein are methods of treating or preventing a viral infection in a subject comprising administering a compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, wherein the subject is not being treated with chloroquine, or an analog or salt thereof.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to the U.S. Provisional PatentApplication No. 63/032,321, filed May 29, 2021, which is incorporatedherein in its entirety for all purposes.

BACKGROUND

Preventing or treating some Arenaviridae, Coronaviridae, Filoviridae,Flaviviridae, Orthomyxovirus, Pneumoviridae, and Paramyxoviridae viralinfections present challenges due to a lack of vaccine or post-exposuretreatment modality for preventing or managing infections caused byviruses from these families. In some cases, patients only receivesupportive therapy such as electrolyte and fluid balancing, oxygen,blood pressure maintenance, or treatment for secondary infections.

The compound (S)-2-ethylbutyl2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, referred to herein as the compound ofFormula Ia, is known to exhibit antiviral properties against severalviral families, including Arenaviridae, Coronaviridae, Filoviridae,Paramyxoviridae, and Flaviviridae viruses (see e.g. Warren, T. et al.,Nature (2016) 531:381-385; Lo M K, et al. Sci. Reports 2017; 7:43395;Sheahan T P, et al. Sci. Transl. Med. 2017; 9:eaa13653; Agostini M L, etal. MBio 2018; 9(2):e00221-18; Cell Research (2020) 30:269-271, and WO2017/184668). There is a need to develop methods of treating viralinfections comprising the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof.

Methods of treating a viral infection comprising the compound of FormulaIa, or a pharmaceutically acceptable salt thereof, in a human in needthereof should avoid other agents that decrease, retard, or attenuatethe antiviral activity of the compound.

BRIEF SUMMARY

In some embodiments, the present disclosure provides a method oftreating a viral infection in a human in need thereof, the methodcomprising administering to the human a therapeutically effective amountof a compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof:

wherein the human is not being treated with chloroquine, or an analog orsalt thereof, thereby treating the viral infection.

In some embodiments, the present disclosure provides a method ofoptimizing a plasma or blood concentration of a compound of Formula II,or a pharmaceutically acceptable salt thereof, in a human in needthereof:

the method comprising administering to the human an antiviral compound,wherein the human has not been administered chloroquine, or an analog orsalt thereof, the antiviral compound is converted to the compound ofFormula II upon administration to the human, and the plasma or bloodconcentration of the compound of Formula II is optimized in the absenceof chloroquine, or an analog or salt thereof.

In some embodiments, the present disclosure provides a method ofoptimizing a plasma or blood concentration of a compound of Formula II,or a pharmaceutically acceptable salt thereof, in a human in needthereof, the method comprising: (a) administering to the human acompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, (b) measuring the plasma or blood concentrationof the compound of Formula II in the human; and (c) adjusting anyremaining doses of the compound of Formula I, Formula Ia, or Formula Ib,to optimize the plasma or blood concentration of the compound of FormulaII in the human.

In some embodiments, the present disclosure provides a method ofdetermining a delivery dose of a compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof, for treatinga viral infection in a human in need thereof, the method comprising: (a)providing an original dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof; (b)determining whether the human has been administered chloroquine, or ananalog or salt thereof; and (c1) if the human has been administeredchloroquine, or an analog or salt thereof, increasing the original doseof the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, to determine the deliverydose, or (c2) if the human has not been administered chloroquine, or ananalog or salt thereof, selecting the original dose of the compound ofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptablesalt thereof, as the delivery dose.

In some embodiments, the present disclosure provides a method of forminga compound of Formula II in a human in need thereof, comprisingadministering to the human a therapeutically effective amount of acompound of Formula Ia, and instructing the human not to takechloroquine, or an analog or salt thereof, wherein the compound ofFormula Ia is metabolized to the compound of Formula II in the absenceof chloroquine, or an analog or salt thereof, wherein the compound ofFormula II has the structure:

andwherein the compound of Formula Ia has the structure:

In some embodiments, the present disclosure provides is a method ofreducing the risk of decreased efficacy of the compound of Formula Ia,or a pharmaceutically acceptable salt thereof, in a human suffering froma viral infection, the method comprising:

-   (a) determining if the human has taken chloroquine, or an analog or    salt thereof, prior to administration of the compound of Formula Ia,    or a pharmaceutically acceptable salt thereof, (b) instructing the    human not to take chloroquine, or an analog or salt thereof, while    being treated with the compound of Formula Ia, or a pharmaceutically    acceptable salt thereof, and (c) administering the compound of    Formula Ia, or a pharmaceutically acceptable salt thereof, to the    human, thereby reducing the risk of decreased efficacy of the    compound of Formula Ia, or a pharmaceutically acceptable salt    thereof.

In some embodiments, the present disclosure provides a method ofpreventing a contraindication in a human suffering from a viralinfection, the method comprising: (a) determining if the human has takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof, (b) instructing the human not to take chloroquine, or an analogor salt thereof, while being treated with the compound of Formula Ia, ora pharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby preventing a contraindication in the human.

In some embodiments, the present disclosure provides a method ofmaintaining efficacy of a compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, in a human suffering from a viral infection,the method comprising: (a) determining if the human has takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof, (b) instructing the human not to take chloroquine, or an analogor salt thereof, while being treated with the compound of Formula Ia, ora pharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby maintaining efficacy of the compound of FormulaIa, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method ofreducing the risk of a reduced plasma concentration of a compound ofFormula II, in a human suffering from a viral infection, the methodcomprising: (a) determining if the human has taken chloroquine, or ananalog or salt thereof, prior to administration of the compound ofFormula Ia, or a pharmaceutically acceptable salt thereof, (b)instructing the human not to take chloroquine, or an analog or saltthereof, while being treated with the compound of Formula Ia, or apharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby reducing the risk of a reduced plasmaconcentration of the compound of Formula II.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Shows the effect of chloroquine (CQ) or hydroxychloroquine (HCQ)on the Formula Ia triphosphate (TP) formation in A549-hACE2 cells.

FIG. 2. Shows the effect of CQ or HCQ on the Formula Ia triphosphate(TP) formation in NHBE cultures.

FIG. 3. Shows the effect of CQ or HCQ on the Formula Ia triphosphate(TP) formation in HEp-2 cells.

FIG. 4A. Shows SARS-CoV-2 antiviral data for the compound of Formula Iain combination with CQ in A549-hACE2 cells. FIG. 4B. Shows SARS-CoV-2antiviral data for the compound of Formula Ia in combination with HCQ inA549-hACE2 cells.

DETAILED DESCRIPTION I. General

The present disclosure provides a method of treating a viral infectionin a subject, comprising administering to the subject a compound ofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptablesalt thereof, wherein the subject is not being treated with chloroquine,or an analog or salt thereof.

II. Definitions

A “compound of the disclosure” refers to a compound that is administeredto a subject in a method as described herein, and includes compounds ofFormula I, Formula Ia, Formula Ib, or a pharmaceutically acceptable saltthereof.

“Pharmaceutically acceptable” or “physiologically acceptable” refer tocompounds, salts, compositions, dosage forms and other materials whichare useful in preparing a pharmaceutical composition that is suitablefor veterinary or human pharmaceutical use.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutical composition” refers to a formulation of a compound ofthe disclosure and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, for example,humans. Such a medium includes all pharmaceutically acceptableexcipients therefor.

“Effective amount” or “therapeutically effective amount” refers to anamount of a compound of the disclosure, which when administered to apatient in need thereof, is sufficient to effect treatment fordisease-states, conditions, or disorders for which the compounds haveutility. Such an amount would be sufficient to elicit the biological ormedical response of a tissue system, or patient that is sought by aresearcher or clinician. The amount of a compound of the disclosurewhich constitutes a therapeutically effective amount will vary dependingon such factors as the compound and its biological activity, thecomposition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of the treatment, the type of disease-state or disorder beingtreated and its severity, drugs used in combination with orcoincidentally with the compounds of the disclosure, and the age, bodyweight, general health, sex and diet of the patient. Such atherapeutically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, thestate of the art, and this disclosure.

“Treatment” or “treating” or “treat” refers to an approach for obtainingbeneficial or desired results including clinical results. Beneficial ordesired clinical results may include one or more of the following: a)inhibiting the disease or condition (e.g., decreasing one or moresymptoms resulting from the disease or condition, and/or diminishing theextent of the disease or condition); b) slowing or arresting thedevelopment of one or more clinical symptoms associated with the diseaseor condition (e.g., stabilizing the disease or condition, preventing ordelaying the worsening or progression of the disease or condition,and/or preventing or delaying the spread (e.g., metastasis) of thedisease or condition); and/or c) relieving the disease, that is, causingthe regression of clinical symptoms (e.g., ameliorating the diseasestate, providing partial or total remission of the disease or condition,enhancing effect of another medication, delaying the progression of thedisease, increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compositions may, in some embodiments, be administeredto a subject (including a human) who is at risk or has a family historyof the disease or condition.

“Subject” or “patient” refer to an animal, such as a mammal, including ahuman, that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject or thepatient is a mammal. In some embodiments, the subject or the patient ishuman; a domestic animal like a dog or a cat; a farm animal such as acow, horse, sheep, goat or pig; or a laboratory animal such as a mouse,rat, hamster, guinea pig, pig, rabbit, dog, or monkey. In someembodiments, the subject or the patient is a human.

“Human in need thereof” refers to a human who may have or is suspectedto have diseases or conditions that would benefit from certaintreatment; for example, being treated with the compounds disclosedherein according to the present application to treat a viral infection.

III. Methods of Use

The present disclosure also provides a method of treating or preventinga viral infection in a human in need thereof, comprising administering acompound described herein.

In some embodiments, the present disclosure provides a method oftreating a viral infection in a human in need thereof, the methodcomprising administering to the human a therapeutically effective amountof a compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof:

wherein the human is not being treated with chloroquine, or an analog orsalt thereof, thereby treating the viral infection.

In some embodiments, the present disclosure provides a method ofconfirming the administration of the compound of Formula I, Formula Ia,or Formula Ib to a human, comprising identifying a compound of FormulaII, or a salt thereof, in a biological sample obtained from the human.In some embodiments, the human is not being treated with chloroquine, oran analog or salt thereof. In some embodiments, the human has not beenpreviously treated with chloroquine, or an analog or salt thereof,before the administering of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the biological sample is derived from plasma or blood.

In some embodiments, the present disclosure provides a method ofmeasuring the rate of metabolism of the compound of Formula I, FormulaIa, or Formula Ib in a human, comprising measuring the amount of acompound of Formula II, or a salt thereof, in the human at one or moretime points after administration of compound of Formula I, Formula Ia,or Formula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the human has not been previously treated with chloroquine,or an analog or salt thereof, before the administering of the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the amount of the compoundof Formula II, or a salt thereof, is measured from a biological sampleobtained from the human. In some embodiments, the amount of the compoundof Formula II, or a salt thereof, is measured from a blood sample. Insome embodiments, the amount of the compound of Formula II, or a saltthereof, is measured from a plasma sample.

In some embodiments, the present disclosure provides a method ofdetermining the prophylactic or therapeutic response of a human in thetreatment of a viral infection comprising measuring the amount of acompound of Formula II, or a salt thereof, in the human at one or moretime points after administration of a compound of Formula I, Formula Ia,or Formula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the human has not been previously treated with chloroquine,or an analog or salt thereof, before the administering of the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the amount of the compoundof Formula II, or a salt thereof, is measured from a biological sampleobtained from the human. In some embodiments, the amount of the compoundof Formula II, or a salt thereof, is measured from a blood sample. Insome embodiments, the amount of the compound of Formula II, or a saltthereof, is measured from a plasma sample.

A. Chloroquine Administration

The present methods provide treatment of a human that does not have anappreciable systemic concentration of chloroquine, or an analog or saltthereof. In some embodiments, the human in need thereof has not beenpreviously treated with chloroquine, or an analog or salt thereof,before the administering of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof.

In some embodiments, the human has been previously treated withchloroquine, or an analog or salt thereof. In some embodiments, thehuman in need thereof has not been treated with chloroquine, or ananalog or salt thereof, for a period of time before the administering ofthe compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof. In some embodiments, theperiod of time between the treatment with chloroquine, or an analog orsalt thereof, and the administration of the compound of the disclosureallows for a decrease in the systemic concentration of the chloroquine,or an analog or salt thereof, such that the antiviral activity of thecompound of the disclosure is not decreased. For example, the period oftime between the treatment with chloroquine, or an analog or saltthereof, and the administration of the compound of the disclosure canallow for a decrease in the plasma concentration of the chloroquine, oran analog or salt thereof, as a result of clearance or metabolism.

In some embodiments, the period of time between the treatment withchloroquine, or an analog or salt thereof, and the administration of thecompound of the disclosure is at least 1 day, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days,180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 days.In some embodiments, the period of time between the treatment withchloroquine, or an analog or salt thereof, and the administration of thecompound of the disclosure is at least 14 days. In some embodiments, theperiod of time between the treatment with chloroquine, or an analog orsalt thereof, and the administration of the compound of the disclosureis at least 28 days. In some embodiments, the period of time between thetreatment with chloroquine, or an analog or salt thereof, and theadministration of the compound of the disclosure is at least 40 days. Insome embodiments, the period of time between the treatment withchloroquine or analog thereof and the administration of the compound ofthe disclosure is at least 50 days. In some embodiments, the period oftime between the treatment with chloroquine, or an analog or saltthereof, and the administration of the compound of the disclosure is atleast 60 days. In some embodiments, the period of time between thetreatment with chloroquine, or an analog or salt thereof, and theadministration of the compound of the disclosure is at least 90 days. Insome embodiments, the period of time between the treatment withchloroquine, or an analog or salt thereof, and the administration of thecompound of the disclosure is at least 120 days. In some embodiments,the period of time between the treatment with chloroquine, or an analogor salt thereof, and the administration of the compound of thedisclosure is at least 180 days. In some embodiments, the period of timebetween the treatment with chloroquine, or an analog or salt thereof,and the administration of the compound of the disclosure is at least 365days.

In some embodiments, the period of time between the treatment withchloroquine, or an analog or salt thereof, and the administration of thecompound of the disclosure is at least 30 mins, at least 1 hour, atleast 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, atleast 8 hours, at least 10 hours, at least 12 hours, at least 14 hours,at least 16 hours, at least 20 hours, or at least 24 hours.

In some embodiments, the human has been administered chloroquine, or ananalog or salt thereof, in from about 1 days to about 365 days prior toreceiving a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof, or from about1 day to about 14 days, from about 1 day to about 21 days, from about 1day to about 30 days, from about 1 day to about 45 days, from about 10days to about 45 days, from about 14 days to about 45 days, from about21 days to about 45 days, from about 28 days to about 45 days, fromabout 30 days to about 45 days, 10 days to about 60 days, from about 14days to about 60 days, from about 21 days to about 60 days, from about28 days to about 60 days, from about 30 days to about 60 days, fromabout 40 days to about 60 days, from about 10 days to about 90 days,from about 14 days to about 90 days, from about 21 days to about 90days, from about 28 days to about 90 days, from about 30 days to about90 days, from about 40 days to about 90 days, from about 10 days toabout 365 days, from about 14 days to about 365 days, from about 21 daysto about 365 days, from about 28 days to about 365 days, from about 30days to about 365 days, or from about 60 days to about 365 days, priorto receiving a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the human has been administered chloroquine, or an analogor salt thereof, in from about 30 days to about 60 days prior toreceiving a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the human has been administered chloroquine, or an analogor salt thereof, in from about 21 days to about 45 days prior toreceiving a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof.

In some embodiments, the human has not been administered chloroquine, oran analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours,4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20hours of receiving a first dose of the compound of Formula I, FormulaIa, or Formula Ib, or a pharmaceutically acceptable salt thereof. Insome embodiments, the human has not been administered chloroquine, or ananalog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days,210 days, 240 days, 270 days, 300 days, 330 days, or 365 days ofreceiving a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof.

In some embodiments, the human has not been administered chloroquine, oran analog or salt thereof, within 1 day of receiving a first dose of thecompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the human has not beenadministered chloroquine, or an analog or salt thereof, within 2 days ofreceiving a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the human has not been administered chloroquine, or ananalog or salt thereof, within 5 days of receiving a first dose of thecompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the human has not beenadministered chloroquine, or an analog or salt thereof, within 7 days ofreceiving a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof. In someembodiments, the human has not been administered chloroquine, or ananalog or salt thereof, within 10 days of receiving the first dose ofthe compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof. In some embodiments, the humanhas not been administered chloroquine, or an analog or salt thereof,within 90 days of receiving the first dose of the compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof. In some embodiments, the human has not been administeredchloroquine, or an analog or salt thereof, within 365 days of receivingthe first dose of the compound of Formula I, Formula Ia, or Formula Ib,or a pharmaceutically acceptable salt thereof.

In some embodiments, the method further comprises instructing the humannot to take chloroquine, or an analog or salt thereof, during thetreatment of the viral infection.

In some embodiments, the method further comprises instructing the humanto wait from about 1 day to about 365 days after taking chloroquine, oran analog or salt thereof, before administering the compound of FormulaI, Formula Ia or Formula Ib, or pharmaceutically acceptable saltthereof, or from about 1 day to about 4 days, from about 1 day to about7 days, from about 1 day to about 10 days, from about 1 day to about 14days, from about 10 days to about 45 days, from about 14 days to about45 days, from about 21 days to about 45 days, from about 28 days toabout 45 days, from about 30 days to about 45 days, 10 days to about 60days, from about 14 days to about 60 days, from about 21 days to about60 days, from about 28 days to about 60 days, from about 30 days toabout 60 days, from about 40 days to about 60 days, from about 10 daysto about 90 days, from about 14 days to about 90 days, from about 21days to about 90 days, from about 28 days to about 90 days, from about30 days to about 90 days, from about 40 days to about 90 days, fromabout 10 days to about 365 days, from about 14 days to about 365 days,from about 21 days to about 365 days, from about 28 days to about 365days, from about 30 days to about 365 days, or from about 60 days toabout 365 days, after taking chloroquine, or an analog or salt thereof,before administering the compound of Formula I, Formula Ia or FormulaIb, or pharmaceutically acceptable salt thereof.

In some embodiments, the method further comprises instructing the humanto wait after taking chloroquine, or an analog or salt thereof, beforeadministering the compound of Formula I, Formula Ia or Formula Ib, orpharmaceutically acceptable salt thereof. In some embodiments, themethod further comprises instructing the human to wait at least 1 day, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days,14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90 days,120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300 days,330 days, or 365 days after taking chloroquine, or an analog or saltthereof, before administering the compound of Formula I, Formula Ia orFormula Ib, or pharmaceutically acceptable salt thereof.

In some embodiments, the method further comprises instructing the humanto wait from about 30 mins to about one day after taking chloroquine, oran analog or salt thereof, before administering the compound of FormulaI, Formula Ia or Formula Ib, or pharmaceutically acceptable saltthereof. For example to wait for at least 30 mins, at least 1 hour, atleast 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, atleast 8 hours, at least 10 hours, at least 12 hours, at least 14 hours,at least 16 hours, at least 20 hours, or at least 24 hours beforeadministering the compound of Formula I, Formula Ia or Formula Ib, orpharmaceutically acceptable salt thereof.

In some embodiments, the method further comprises instructing the humanto wait after taking chloroquine, or an analog or salt thereof, beforeadministering the compound of Formula Ia, or pharmaceutically acceptablesalt thereof. In some embodiments, the method further comprisesinstructing the human to wait at least 1 day, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28days, 30 days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days,180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365 daysafter taking chloroquine, or an analog or salt thereof, beforeadministering the compound of Formula Ia, or pharmaceutically acceptablesalt thereof.

In some embodiments, the method further comprises instructing the humanto wait from about 30 mins to about one day after taking chloroquine, oran analog or salt thereof, before administering the compound of FormulaIa, or pharmaceutically acceptable salt thereof. For example to wait forat least 30 mins, at least 1 hour, at least 2 hours, at least 3 hours,at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours,at least 12 hours, at least 14 hours, at least 16 hours, at least 20hours, or at least 24 hours before administering the compound of FormulaIa, or pharmaceutically acceptable salt thereof.

In some embodiments, the human is not administered chloroquine, or ananalog or salt thereof, during the treatment of the viral infection. Insome embodiments, the method further comprises instructing the human tonot administer chloroquine, or an analog or salt thereof, during thetreatment of the viral infection.

In some embodiments, the method comprises administering to the human atherapeutically effective amount of a compound of Formula I, Formula Ia,or Formula Ib, or a pharmaceutically acceptable salt thereof, providedthe human has not been administered chloroquine, or an analog or saltthereof, prior to the start of treatment, thereby treating the viralinfection. In some embodiments, the human has not been administeredchloroquine, or an analog or salt thereof, for at least 1 day, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days,21 days, 28 days, 30 days, 45 days, 60 days, 90 days, 120 days, 150days, 180 days, 210 days, 240 days, 270 days, 300 days, 330 days, or 365days prior to the start of treatment. In some embodiments, the human hasnot been administered chloroquine, or an analog or salt thereof, for atleast 1 day prior to the start of treatment. In some embodiments, thehuman has not been administered chloroquine, or an analog or saltthereof, for at least 10 days prior to the start of treatment. In someembodiments, the human has not been administered chloroquine, or ananalog or salt thereof, for at least 30 mins, at least 1 hour, at least2 hours, at least 3 hours, at least 4 hours, at least 6 hours, at least8 hours, at least 10 hours, at least 12 hours, at least 14 hours, atleast 16 hours, at least 20 hours, or at least 24 hours prior to thestart of treatment.

Various techniques can be used to determine whether or not a human inneed thereof has previously taken chloroquine, or an analog or saltthereof. Non-limiting techniques include self-reporting, interviewingthe human, reviewing the human's medical records, or measuring the levelof chloroquine, or a metabolite, analog or salt thereof, in the plasmaor blood in the human.

The human in need of treatment for a viral infection may also beevaluated for plasma or blood concentration of the chloroquine, or ananalog or salt thereof, prior to administration of the compound of thedisclosure, such as a compound of Formula I, Formula Ia, or Formula Ib,or a pharmaceutically acceptable salt thereof. In some embodiments, ahuman in need of treatment for a viral infection has a plasma or bloodconcentration measured prior to administration of the compound of thedisclosure.

Concentrations of chloroquine, or an analog or salt thereof, in humanplasma or blood can be measured by any method known in the art. See, forexample, Walker, O. et al. British Journal Clinical Pharmacology (1983),vol. 16, pages 701-705; Kaewkhao, K. et al. Bioanalysis (2019), vol.11(5), pages 333-347; Durcan, L. et al. Journal of Rheumatology (2015),vol. 42(11), pages 2092-2097; Munster, T. et al. Arthritis Rheumatology(2002), vol. 46(6), pages 1460-1469.

In some embodiments, the human has a plasma or blood concentration ofthe chloroquine, or an analog or salt thereof, of from about 0.1 ng/mLto about 5000 ng/mL at the time a first dose of the compound of FormulaI, Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof, is administered to the human, or from about 0.1 ng/mL to about4000 ng/mL, from about 0.1 ng/mL to about 3000 ng/mL, from about 0.1ng/mL to about 2000 ng/mL, from about 0.1 ng/mL to about 1000 ng/mL,from about 0.1 ng/mL to about 500 ng/mL, from about 0.1 ng/mL to about400 ng/mL, from about 0.1 ng/mL to about 300 ng/mL, from about 0.1 ng/mLto about 200 ng/mL, from about 0.1 ng/mL to about 100 ng/mL, from about0.1 ng/mL to about 80 ng/mL, from about 0.1 ng/mL to about 60 ng/mL,from about 0.1 ng/mL to about 50 ng/mL, from about 0.1 ng/mL to about 40ng/mL, from about 0.1 ng/mL to about 30 ng/mL, from about 0.1 ng/mL toabout 20 ng/mL, or from about 0.1 ng/mL to about 10 ng/mL, from about 5ng/mL to about 4000 ng/mL, from about 5 ng/mL to about 3000 ng/mL, fromabout 5 ng/mL to about 2000 ng/mL, from about 5 ng/mL to about 1000ng/mL, from about 5 ng/mL to about 500 ng/mL, from about 5 ng/mL toabout 400 ng/mL, from about 5 ng/mL to about 300 ng/mL, from about 5ng/mL to about 200 ng/mL, from about 5 ng/mL to about 100 ng/mL, fromabout 5 ng/mL to about 80 ng/mL, from about 5 ng/mL to about 60 ng/mL,from about 5 ng/mL to about 50 ng/mL, from about 5 ng/mL to about 40ng/mL, from about 5 ng/mL to about 30 ng/mL, from about 5 ng/mL to about20 ng/mL, or from about 5 ng/mL to about 10 ng/mL, at the time a firstdose of the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, is administered to the human.In some embodiments, the human has a plasma or blood concentration ofthe chloroquine, or an analog or salt thereof, of from about 0.1 ng/mLto about 50 ng/mL, at the time a first dose of the compound of thedisclosure is administered to the human.

In some embodiments, the human has a plasma or blood concentration ofthe chloroquine, or an analog or salt thereof, of less than 5000 ng/mLat the time a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof, isadministered to the human, or less than 4000 ng/mL, 3000 ng/mL, 2000ng/mL, 1000 ng/mL, 500 ng/mL, 400 ng/mL, 300 ng/mL, 200 ng/mL, 100ng/mL, 80 ng/mL, 60 ng/mL, 50 ng/mL, 45 ng/mL, 40 ng/mL, 35 ng/mL, 30ng/mL, 25 ng/mL, 20 ng/mL, 15 ng/mL, 10 ng/mL, or 5 ng/mL at the time afirst dose of the compound of the disclosure is administered to thehuman.

In some embodiments, the human has a plasma or blood concentration ofthe chloroquine, or an analog or salt thereof, of less than 50 ng/mL atthe time a first dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof, isadministered to the human.

“Chloroquine, or an analog or salt thereof” refers to chloroquine (alsoknown as CQ, N′-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamineand CAS Number 54-05-7), hydroxychloroquine (also known as HCQ,2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol and CASNumber 118-42-3), and metabolites thereof in the plasma afteradministration to a human. Members include chloroquine,desethylchloroquine (also known as DCQ,4-N-(7-chloroquinolin-4-yl)-1-N-ethylpentane-1,4-diamine and CAS Number1476-52-4), hydroxychloroquine, desethylhydroxychloroquine (also knownas DHCQ, cletoquine,2-[4-[(7-chloroquinolin-4-yl)amino]pentylamino]ethanol, and CAS Number4298-15-1), and bidesethylhydroxychloroquine (also known as BDCQ), or apharmaceutically acceptable salt thereof. Illustrative examples includechloroquine, or a pharmaceutically acceptable salt thereof. An exampleis chloroquine phosphate, commercially available as Aralen®. Chloroquinehas the chemical structure:

An alternative example includes hydroxychloroquine, or apharmaceutically acceptable salt thereof. An example ishydroxychloroquine sulfate, commercially available as Plaquenil®.Hydroxychloroquine has the chemical structure:

In some embodiments, the chloroquine, or an analog or salt thereof, ischloroquine, desethylchloroquine, hydroxychloroquine,desethylhydroxychloroquine, or bidesethylhydroxychloroquine, or apharmaceutically acceptable salt thereof. In some embodiments, thechloroquine, or an analog or salt thereof, is chloroquine,hydroxychloroquine, or a pharmaceutically acceptable salt thereof. Insome embodiments, the chloroquine, or an analog or salt thereof, ischloroquine, or a pharmaceutically acceptable salt thereof. For example,the chloroquine, or an analog or salt thereof, can be chloroquinephosphate. In some embodiments, the chloroquine, or an analog or saltthereof, is hydroxychloroquine, or a pharmaceutically acceptable saltthereof. For example, the chloroquine, or an analog or salt thereof, canbe hydroxychloroquine sulfate.

B. Compounds

The present disclosure includes use of antiviral compounds that whenadministered to a human in need thereof produce the compound of FormulaII, or a pharmaceutically acceptable salt thereof.

The present disclosure also includes use of compounds of Formula I,Formula Ia and Formula Ib, or a pharmaceutically acceptable saltthereof.

The compound of Formula I was described in WO2012/012776. The IUPAC namefor the compound of Formula I is 2-ethylbutyl((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.The compound of Formula I, or a pharmaceutically acceptable saltthereof, has the structure:

The compound of Formula Ia was described in WO2016/069826. The IUPACname for the compound of Formula Ia is (S)-2-ethylbutyl2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyn-olo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate,and the CAS Registry Number is 1809249-37-3. The compound of Formula Iais also referred to as remdesivir and GS-5734. The compound of FormulaIa, or a pharmaceutically acceptable salt thereof, has the structure:

The compound of Formula Ib was described in WO2016/069826. The IUPACname for the compound of Formula Ib is (S)-2-ethylbutyl2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate.The compound of Formula Ib, or a pharmaceutically acceptable saltthereof, has the structure:

In some embodiments, administering a compound of Formula I, Formula Ia,or Formula Ib, or a pharmaceutically acceptable salt thereof, to a humanin need thereof produces a compound of Formula II or a pharmaceuticallyacceptable salt thereof:

The compound of Formula I, Formula Ia, or Formula Ib can be used in anysuitable form. For example, the compound of Formula I, Formula Ia, orFormula Ib can be amorphous or crystalline. In some embodiments, thecompound of Formula I, Formula Ia, or Formula Ib is amorphous. In someembodiments, the compound of Formula I, Formula Ia, or Formula Ib iscrystalline.

Crystalline forms of the compound of Formula Ia useful in the methodsand compositions of the present disclosure are described in U.S. PatentApplication Publication No. 2018/0346504. For example, the compound ofFormula Ia can be crystalline Form I, Form II, Form III, or Form IV asdescribed in U.S. Patent Application Publication No. 20180346504, or acombination thereof. In some embodiments, the compound of Formula Ia iscrystalline.

The compounds of Formula I, Formula Ia and Formula Ib, or apharmaceutically acceptable salt thereof, can be combined with one ormore pharmaceutically acceptable excipients. In some embodiments, thepharmaceutically acceptable excipient comprises an aqueous vehicle. Insome embodiments, the pharmaceutical compositions provided hereincomprise the compound of Formula I, or a pharmaceutically acceptablesalt thereof, and an aqueous vehicle. In some embodiments, thepharmaceutical compositions provided herein comprise the compound ofFormula Ia, or a pharmaceutically acceptable salt thereof, and anaqueous vehicle. In some embodiments, the pharmaceutical compositionsprovided herein comprise the compound of Formula Ib, or apharmaceutically acceptable salt thereof, and an aqueous vehicle. Theaqueous vehicle comprises water and optionally one or more componentsselected from a co-solvent, a surfactant, a suspending agent, a tonicityagent, a buffer, a cyclodextrin, and an anti-microbial agent orpreservative. Exemplary formulations may be found in U.S. PatentApplication Publication No. 2019/0083525.

In some embodiments, the method of treating the viral infection in thehuman in need thereof comprises administering to the human the compoundof Formula I, or a pharmaceutically acceptable salt thereof:

In some embodiments, the method comprises administering the compound ofFormula I.

In some embodiments, the method of treating the viral infection in thehuman in need thereof, comprises administering to the human a compoundof Formula Ia, or a pharmaceutically acceptable salt thereof:

In some embodiments, the method comprises administering the compound ofFormula Ia.

In some embodiments, the method of treating the viral infection in thehuman in need thereof comprises administering to the human a compound ofFormula Ib, or a pharmaceutically acceptable salt thereof:

In some embodiments, the method comprises administering the compound ofFormula Ib.

The compound of the disclosure can be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, rectal, nasal (including inhalation), pulmonary, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), implants, and the like. It will be appreciated that thepreferred route may vary, for example, with the condition of the human.

In some embodiments, the compound of Formula I, Formula Ia, or FormulaIb, or a pharmaceutically acceptable salt thereof, is administered byinhalation or intravenously. In some embodiments, the compound ofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptablesalt thereof, is administered intravenously. In some embodiments, thecompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, is administered by inhalation.

In some embodiments, the compound of Formula I, Formula Ia, or FormulaIb, or a pharmaceutically acceptable salt thereof, is administered oncedaily or twice daily. In some embodiments, the compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof, is administered once daily.

In some embodiments, the human weighs at least 40 kg, and the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, is administered in the first dose of 150-250 mgon day 1, and administered in a second dose of 50-150 mg on each of thefollowing 4 days. In some embodiments, the second dose of 50-150 mg isadministered for an additional 1 to 5 days. In some embodiments, thehuman weighs at least 40 kg, and the compound of Formula I, Formula Ia,or Formula Ib, or a pharmaceutically acceptable salt thereof, isadministered in the first dose of 150-250 mg on day 1, and administeredin a second dose of 50-150 mg on each of the following 4, 5, 6, 7, 8, or9 days. In some embodiments, the human weighs at least 40 kg, and thecompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, is administered in the first dose of 150-250 mgon day 1, and administered in a second dose of 50-150 mg on each of thefollowing 9 days. In some embodiments, the compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof, is administered once daily. In some embodiments, the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, is administered over from about 30 to about 120minutes.

In some embodiments, the human weighs at least 40 kg, and the compoundof Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, is administered intravenously in the first doseof 200 mg on day 1, and administered intravenously in a second dose of100 mg on each of the following 4 days. In some embodiments, the seconddose of 100 mg is administered for an additional 1 to 5 days. In someembodiments, the human weighs at least 40 kg, and the compound ofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptablesalt thereof, is administered intravenously in the first dose of 200 mgon day 1, and administered intravenously in a second dose of 100 mg oneach of the following 4, 5, 6, 7, 8, or 9 days. In some embodiments, thehuman weighs at least 40 kg, and the compound of Formula I, Formula Ia,or Formula Ib, or a pharmaceutically acceptable salt thereof, isadministered intravenously in the first dose of 200 mg on day 1, andadministered intravenously in a second dose of 100 mg on each of thefollowing 9 days. In some embodiments, the compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof, is administered intravenously once daily. In some embodiments,the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, is administered intravenouslyover from about 30 to about 120 minutes.

In some embodiments, the human weighs at least 40 kg, and the compoundof Formula Ia, or a pharmaceutically acceptable salt thereof, isadministered in the first dose of 150-250 mg on day 1, and administeredin a second dose of 50-150 mg on each of the following 4 days. In someembodiments, the second dose of 50-150 mg is administered for anadditional 1 to 5 days. In some embodiments, the human weighs at least40 kg, and the compound of Formula Ia, or a pharmaceutically acceptablesalt thereof, is administered in the first dose of 150-250 mg on day 1,and administered in a second dose of 50-150 mg on each of the following4, 5, 6, 7, 8, or 9 days. In some embodiments, the human weighs at least40 kg, and the compound of Formula Ia, or a pharmaceutically acceptablesalt thereof, is administered in the first dose of 150-250 mg on day 1,and administered in a second dose of 50-150 mg on each of the following9 days. In some embodiments, the compound of Formula Ia, or apharmaceutically acceptable salt thereof, is administered once daily. Insome embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, is administered over from about 30 to about 120minutes.

In some embodiments, the human weighs at least 40 kg, and the compoundof Formula Ia, or a pharmaceutically acceptable salt thereof, isadministered intravenously in the first dose of 200 mg on day 1, andadministered intravenously in a second dose of 100 mg on each of thefollowing 4 days. In some embodiments, the second dose of 100 mg isadministered for an additional 1 to 5 days. In some embodiments, thehuman weighs at least 40 kg, and the compound of Formula Ia, or apharmaceutically acceptable salt thereof, is administered intravenouslyin the first dose of 200 mg on day 1, and administered intravenously ina second dose of 100 mg on each of the following 4, 5, 6, 7, 8, or 9days. In some embodiments, the human weighs at least 40 kg, and thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,is administered intravenously in the first dose of 200 mg on day 1, andadministered intravenously in a second dose of 100 mg on each of thefollowing 9 days. In some embodiments, the compound of Formula Ia, or apharmaceutically acceptable salt thereof, is administered intravenouslyonce daily. In some embodiments, the compound of Formula Ia, or apharmaceutically acceptable salt thereof, is administered intravenouslyover from about 30 to about 120 minutes.

In some embodiments, the human weighs from 3.5 kg to less than 40 kg,and the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, is administered in the firstdose of 2.5-10 mg/kg on day 1, and administered in a second dose of 1-5mg/kg on each of the following 4 days. In some embodiments, the seconddose of 1-5 mg/kg is administered for an additional 1 to 5 days. In someembodiments the human weighs from 3.5 kg to less than 40 kg, and thecompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, is administered in the first dose of 2.5-10mg/kg on day 1, and administered in a second dose of 1-5 mg/kg on eachof the following 4, 5, 6, 7, 8, or 9 days. In some embodiments the humanweighs from 3.5 kg to less than 40 kg, and the compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof, is administered in the first dose of 2.5-10 mg/kg on day 1, andadministered in a second dose of 1-5 mg/kg on each of the following 9days. In some embodiments, the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof, isadministered once daily. In some embodiments, the compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof, is administered over from about 30 to about 120 minutes.

In some embodiments, the human weighs from 3.5 kg to less than 40 kg,and the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, is administered intravenouslyin the first dose of 5 mg/kg on day 1, and administered intravenously ina second dose of 2.5 mg/kg on each of the following 4 days. In someembodiments, the second dose of 2.5 mg/kg is administered for anadditional 1 to 5 days. In some embodiments the human weighs from 3.5 kgto less than 40 kg, and the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof, isadministered intravenously in the first dose of 5 mg/kg on day 1, andadministered intravenously in a second dose of 2.5 mg/kg on each of thefollowing 4, 5, 6, 7, 8, or 9 days. In some embodiments the human weighsfrom 3.5 kg to less than 40 kg, and the compound of Formula I, FormulaIa, or Formula Ib, or a pharmaceutically acceptable salt thereof, isadministered intravenously in the first dose of 5 mg/kg on day 1, andadministered intravenously in a second dose of 2.5 mg/kg on each of thefollowing 9 days. In some embodiments, the compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof, is administered intravenously once daily. In some embodiments,the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, is administered intravenouslyover from about 30 to about 120 minutes.

In some embodiments, the human weighs from 3.5 kg to less than 40 kg,and the compound of Formula Ia, or a pharmaceutically acceptable saltthereof, is administered in the first dose of 2.5-10 mg/kg on day 1, andadministered in a second dose of 1-5 mg/kg on each of the following 4days. In some embodiments, the second dose of 1-5 mg/kg is administeredfor an additional 1 to 5 days. In some embodiments the human weighs from3.5 kg to less than 40 kg, and the compound of Formula Ia, or apharmaceutically acceptable salt thereof, is administered in the firstdose of 2.5-10 mg/kg on day 1, and administered in a second dose of 1-5mg/kg on each of the following 4, 5, 6, 7, 8, or 9 days. In someembodiments the human weighs from 3.5 kg to less than 40 kg, and thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,is administered in the first dose of 2.5-10 mg/kg on day 1, andadministered in a second dose of 1-5 mg/kg on each of the following 9days. In some embodiments, the compound of Formula Ia, or apharmaceutically acceptable salt thereof, is administered once daily. Insome embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, is administered over from about 30 to about 120minutes.

In some embodiments, the human weighs from 3.5 kg to less than 40 kg,and the compound of Formula Ia, or a pharmaceutically acceptable saltthereof, is administered intravenously in the first dose of 5 mg/kg onday 1, and administered intravenously in a second dose of 2.5 mg/kg oneach of the following 4 days. In some embodiments, the second dose of2.5 mg/kg is administered for an additional 1 to 5 days. In someembodiments, the human weighs from 3.5 kg to less than 40 kg, and thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,is administered intravenously in the first dose of 5 mg/kg on day 1, andadministered intravenously in a second dose of 2.5 mg/kg on each of thefollowing 4, 5, 6, 7, 8, or 9 days. In some embodiments, the humanweighs from 3.5 kg to less than 40 kg, and the compound of Formula Ia,or a pharmaceutically acceptable salt thereof, is administeredintravenously in the first dose of 5 mg/kg on day 1, and administeredintravenously in a second dose of 2.5 mg/kg on each of the following 9days. In some embodiments, the compound of Formula Ia, or apharmaceutically acceptable salt thereof, is administered intravenouslyonce daily. In some embodiments, the compound of Formula Ia, or apharmaceutically acceptable salt thereof, is administered intravenouslyover from about 30 to about 120 minutes.

C. Viral Infections

Any suitable viral infection can be treated by the method of the presentdisclosure. In some embodiments, the viral infection is caused by avirus selected from the group consisting of Arenaviridae, Coronaviridae,Filoviridae, Flaviviridae, Pneumoviridae, and Paramyxoviridae.

In some embodiments, the viral infection is caused by an Arenaviridaevirus. In some embodiments, the method of treating an Arenaviridae virusinfection comprises administering a compound of the disclosure, such asa compound of Formula I, Formula Ia, or Formula Ib, or pharmaceuticallyacceptable salt thereof. In some embodiments, the method comprisestreating an Arenaviridae virus infection selected from the groupconsisting of Allpahuayo virus (ALLV), Amapari virus (AMAV), Bear Canyonvirus (BCNV), Catarina virus, Chapare virus, Cupixi virus (CPXV),Dandenong virus, Flexal virus (FLEV), Guanarito virus (GTOV), Ippy virus(IPPYV), Junin virus (JUNV), Kodoko virus, Lassa virus (LASV), Latinovirus (LATV), Lymphocytic choriomeningitis virus (LCMV), Lujo virus,Machupo virus (MACV), Mobala virus (MOBV), Morogoro virus, Mopeia virus(MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus(PICV), Pinhal virus, Pirital virus (PIRV), Sabia virus (SABV), SkinnerTank virus, Tacaribe virus (TCRV), Tamiami virus (TAMV), and WhitewaterArroyo virus (WWAV) by administering a compound of the disclosureprovided herein. In some embodiments, the Arenaviridae virus is Lassa orJunin. In some embodiments, the method comprises treating a Lassa virusinfection by administering a compound of the disclosure provided herein.In some embodiments, the method comprises treating a Junin virusinfection by administering a compound of the disclosure provided herein.

In some embodiments, the viral infection is caused by a Coronaviridaevirus. In some embodiments, the method of treating a Coronaviridae virusinfection comprises administering a compound of the disclosure, such asa compound of Formula I, Formula Ia, or Formula Ib, or pharmaceuticallyacceptable salt thereof. In some embodiments, the Coronaviridae virusinfection is selected from the group consisting of a Severe AcuteRespiratory Syndrome (SARS) infection, SARS-CoV-2 (also known as2019-nCov and COVID-19) infection, Middle Eastern Respiratory Syndrome(MERS) infection, other human coronavirus (229E, NL63, 0C43, HKU1, orWW1) infections, or a zoonotic coronavirus (PEDV or HKU CoV isolatessuch as HKU3, HKU5, or HKU9) infection. In some embodiments, theCoronaviridae virus is SARS, SARS-CoV-2, or MERS. In some embodiments,the Coronaviridae virus is SARS. In some embodiments, the Coronaviridaevirus is SARS-CoV-2. In some embodiments, the Coronaviridae virus isMERS. In some embodiments, the viral infection is caused by a virushaving at least 70% sequence homology a viral polymerase selected fromSARS-CoV polymerase, SARS-CoV-2 polymerase, and MERS polymerase. In someembodiments, the viral infection is caused by a virus having at least80% sequence homology a viral polymerase selected from SARS-CoVpolymerase, SARS-CoV-2 polymerase, and MERS polymerase. In someembodiments, the viral infection is caused by a virus having at least90% sequence homology a viral polymerase selected from SARS-CoVpolymerase, SARS-CoV-2 polymerase, and MERS polymerase. In someembodiments, the viral infection is caused by a virus having at least95% sequence homology a viral polymerase selected from SARS-CoVpolymerase, SARS-CoV-2 polymerase, and MERS polymerase. In someembodiments, the viral infection is caused by a virus having at least97% sequence homology a viral polymerase selected from SARS-CoVpolymerase, SARS-CoV-2 polymerase, and MERS polymerase. In someembodiments, the viral infection is caused by a virus having at least99% sequence homology a viral polymerase selected from SARS-CoVpolymerase, SARS-CoV-2 polymerase, and MERS polymerase.

In some embodiments, the viral infection is caused by a Filoviridaevirus. In some embodiments, the method of treating a Filoviridae virusinfection comprises administering a compound of the disclosure, such asa compound of Formula I, Formula Ia, or Formula Ib, or pharmaceuticallyacceptable salt thereof. In some embodiments, the Filoviridae virus isEbola or Marburg. In some embodiments, the Filoviridae virus is an Ebolavirus. In some embodiments, the Ebola virus is selected from the groupconsisting of: Zaire (i.e. Ebola virus, EBOV), Sudan, Tai Forest,Bundibugyo, and Reston. In some embodiments, the Filoviridae virus is aMarburg virus.

In some embodiments, the viral infection is caused by a Flaviviridaevirus. In some embodiments, the method of treating a Flaviviridae virusinfection comprises administering a compound of the disclosure, such asa compound of Formula I, Formula Ia, or Formula Ib, or pharmaceuticallyacceptable salt thereof. In some embodiments, the Flaviviridae virus isselected from the group consisting of: dengue, yellow fever, West Nile,and Zika. In some embodiments, the method of treating a dengue virusinfection comprises administering a compound of the disclosure providedherein. In some embodiments, the Flaviviridae virus is yellow fever. Insome embodiments, the method of treating a yellow fever virus infectioncomprises administering a compound of the disclosure provided herein. Insome embodiments, the method of treating a West Nile virus infectioncomprises administering a compound of the disclosure provided herein. Insome embodiments, the method of treating a Zika virus infectioncomprises administering a compound of the disclosure provided herein. Insome embodiments, the method of treating a hepatitis C virus infectioncomprises administering a compound of the disclosure provided herein.

In some embodiments, the viral infection is caused by a Pneumoviridaevirus. In some embodiments, the method of treating a Pneumoviridae virusinfection comprises administering a compound of the disclosure, such asa compound of Formula I, Formula Ia, or Formula Ib, or pharmaceuticallyacceptable salt thereof. In some embodiments, the Pneumoviridae virus isrespiratory syncytial virus or human metapneumovirus. In someembodiments, the Pneumoviridae virus is respiratory syncytial virus. Insome embodiments, the Pneumoviridae virus is human metapneumovirus.

In some embodiments, the viral infection is caused by a Paramyxoviridaevirus. In some embodiments, the method of treating a Paramyxoviridaevirus infection comprises administering a compound of the disclosure,such as a compound of Formula I, Formula Ia, or Formula Ib, orpharmaceutically acceptable salt thereof. Paramyxoviridae virusesinclude, but are not limited to Nipah virus, Hendra virus, measles,mumps, and parainfluenza virus. In some embodiments, the Paramyxoviridaevirus is Nipah or parainfluenza virus. In some embodiments, theParamyxoviridae virus is Nipah. In some embodiments, the Paramyxoviridaevirus is parainfluenza.

In some embodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in methods of treating an Arenaviridae virus infection. In someembodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in methods of treating an Arenaviridae virus infection selectedfrom the group of Allpahuayo virus (ALLY), Amapari virus (AMAV), BearCanyon virus (BCNV), Catarina virus, Chapare virus, Cupixi virus (CPXV),Dandenong virus, Flexal virus (FLEV), Guanarito virus (GTOV), Ippy virus(IPPYV), Junin virus (JUNV), Kodoko virus, Lassa virus (LASV), Latinovirus (LATV), Lymphocytic choriomeningitis virus (LCMV), Lujo virus,Machupo virus (MACV), Mobala virus (MOBV), Morogoro virus, Mopeia virus(MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus(PICV), Pinhal virus, Pirital virus (PIRV), Sabia virus (SABV), SkinnerTank virus, Tacaribe virus (TCRV), Tamiami virus (TAMV), and WhitewaterArroyo virus (WWAV) by administering a compound of the disclosureprovided herein. In some embodiments, the Arenaviridae virus is Lassa orJunin. In some embodiments, the present disclosure provides a compoundof the disclosure provided herein, or pharmaceutically acceptable saltthereof, for use in methods of treating a Lassa virus infection. In someembodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in methods of treating a Junin virus infection.

In some embodiments, the present disclosure provides a compound of thedisclosure provided herein for use in methods of treating aCoronaviridae virus infection. In some embodiments, the Coronaviridaevirus infection is selected from the group consisting of a Severe AcuteRespiratory Syndrome (SARS) infection, SARS-CoV-2 (also known as2019-nCov and COVID-19) infection, Middle Eastern Respiratory Syndrome(MERS) infection, other human coronavirus (229E, NL63, 0C43, HKU1, orWW1) infections, or a zoonotic coronavirus (PEDV or HKU CoV isolatessuch as HKU3, HKU5, or HKU9) infection. In some embodiments, theCoronaviridae virus is SARS, SARS-CoV-2, or MERS. In some embodiments,the Coronaviridae virus is SARS. In some embodiments, the presentdisclosure provides a compound of the disclosure provided herein for usein methods of treating a Severe Acute Respiratory Syndrome (SARS)infection. In some embodiments, the Coronaviridae virus is SARS-CoV-2.In some embodiments, the present disclosure provides a compound of thedisclosure provided herein for use in methods of treating a SARS-nCoV-2infection. In some embodiments, the Coronaviridae virus is MERS. In someembodiments, the present disclosure provides a compound of thedisclosure provided herein for use in methods of treating a Middle EastRespiratory Syndrome (MERS) infection.

In some embodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in methods of treating a Filoviridae virus infection. In someembodiments, the Filoviridae virus is Ebola or Marburg. In someembodiments, the Filoviridae virus is an Ebola virus. In someembodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in methods of treating an Ebola virus infection. In someembodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in methods of treating an Ebola virus infection selected fromthe group consisting of: Zaire (i.e. Ebola virus, EBOV), Sudan, TaiForest, Bundibugyo, and Reston. In some embodiments, the Filoviridaevirus is a Marburg virus. In some embodiments, the present disclosureprovides a compound of the disclosure provided herein, orpharmaceutically acceptable salt thereof, for use in methods of treatinga Marburg virus infection.

In some embodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in methods of treating a Flaviviridae virus infection. In someembodiments, the Flaviviridae virus is selected from the groupconsisting of: dengue, yellow fever, West Nile, and Zika. In someembodiments, the Flaviviridae virus is dengue virus. In someembodiments, the Flaviviridae virus is yellow fever. In someembodiments, the Flaviviridae virus is West Nile virus. In someembodiments, the Flaviviridae virus is Zika virus. In some embodiments,the Flaviviridae virus is hepatitis C virus.

In some embodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in a method of treating a Pneumoviridae virus infection. In someembodiments, the Pneumoviridae virus is respiratory syncytial virus orhuman metapneumovirus. In some embodiments, the Pneumoviridae virus is arespiratory syncytial virus. In some embodiments, the Pneumoviridaevirus is human metapneumovirus.

In some embodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in a method of treating a Paramyxoviridae virus infection.Paramyxoviridae viruses include, but are not limited to Nipah virus,Hendra virus, measles, mumps, and parainfluenza virus. In someembodiments, the Paramyxoviridae virus is Nipah or parainfluenza virus.In some embodiments, the Paramyxoviridae virus is Nipah. In someembodiments, the Paramyxoviridae virus is parainfluenza.

In some embodiments, the present disclosure provides the use of acompound of the disclosure provided herein, or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatingan Arenaviridae virus infection. In some embodiments, the presentdisclosure provides the use of a compound of the disclosure providedherein, or pharmaceutically acceptable salt thereof, in the manufactureof a medicament for treating an Arenaviridae virus infection selectedfrom the group of: Allpahuayo virus (ALLY), Amapari virus (AMAV), BearCanyon virus (BCNV), Catarina virus, Chapare virus, Cupixi virus (CPXV),Dandenong virus, Flexal virus (FLEV), Guanarito virus (GTOV), Ippy virus(IPPYV), Junin virus (JUNV), Kodoko virus, Lassa virus (LASV), Latinovirus (LATV), Lymphocytic choriomeningitis virus (LCMV), Lujo virus,Machupo virus (MACV), Mobala virus (MOBV), Morogoro virus, Mopeia virus(MOPV), Oliveros virus (OLVV), Parana virus (PARV), Pichinde virus(PICV), Pinhal virus, Pirital virus (PIRV), Sabia virus (SABV), SkinnerTank virus, Tacaribe virus (TCRV), Tamiami virus (TAMV), and WhitewaterArroyo virus (WWAV). In some embodiments, the Arenaviridae virus isLassa or Junin. In some embodiments, the present disclosure provides theuse of a compound of the disclosure provided herein, or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatinga Lassa virus infection. In some embodiments, the present disclosureprovides the use of a compound of the disclosure provided herein, orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating a Junin virus infection.

In some embodiments, the present disclosure provides the use of acompound of the disclosure provided herein, or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatinga Coronaviridae virus infection. In some embodiments, the Coronaviridaevirus infection is selected from the group consisting of a Severe AcuteRespiratory Syndrome (SARS) infection, SARS-CoV-2 (also known as2019-nCov and COVID-19) infection, Middle Eastern Respiratory Syndrome(MERS) infection, other human coronavirus (229E, NL63, 0C43, HKU1, orWW1) infections, or a zoonotic coronavirus (PEDV or HKU CoV isolatessuch as HKU3, HKU5, or HKU9) infection. In some embodiments, theCoronaviridae virus is SARS, SARS-CoV-2, or MERS. In some embodiments,the Coronaviridae virus is SARS. In some embodiments, the presentdisclosure provides the use of a compound of the disclosure providedherein, or pharmaceutically acceptable salt thereof, in the manufactureof a medicament for treating a SARS infection. In some embodiments, theCoronaviridae virus is SARS-CoV-2. In some embodiments, the presentdisclosure provides the use of a compound of the disclosure providedherein, or pharmaceutically acceptable salt thereof, in the manufactureof a medicament for treating a SARS-nCoV-2 infection. In someembodiments, the Coronaviridae virus is MERS. In some embodiments, thepresent disclosure provides the use of a compound of the disclosureprovided herein, or pharmaceutically acceptable salt thereof, in themanufacture of a medicament for treating a MERS infection.

In some embodiments, the present disclosure provides the use of acompound of the disclosure provided herein, or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatinga Filoviridae virus infection. In some embodiments, the Filoviridaevirus is Ebola or Marburg. In some embodiments, the Filoviridae virus isan Ebola virus. In some embodiments, the present disclosure provides theuse of a compound of the disclosure provided herein, or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatingan Ebola virus infection. In some embodiments, the present disclosureprovides the use of a compound of the disclosure provided herein, orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating an Ebola virus infection selected from the groupconsisting of: Zaire (i.e. Ebola virus, EBOV), Sudan, Tai Forest,Bundibugyo, and Reston. In some embodiments, the present disclosureprovides the use of a compound of the disclosure provided herein, orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating a Marburg virus infection.

In some embodiments, the present disclosure provides the use of acompound of the disclosure provided herein, or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatinga Flaviviridae virus infection. In some embodiments, the Flaviviridaevirus is selected from the group consisting of: dengue, yellow fever,West Nile, and Zika. In some embodiments, the Flaviviridae virus isdengue virus. In some embodiments, the Flaviviridae virus is yellowfever. In some embodiments, the Flaviviridae virus is West Nile virus.In some embodiments, the Flaviviridae virus is Zika virus. In someembodiments, the Flaviviridae virus is hepatitis C virus.

In some embodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in a manufacture of a medicament for treating a Pneumoviridaevirus infection. In some embodiments, the Pneumoviridae virus isrespiratory syncytial virus or human metapneumovirus. In someembodiments, the Pneumoviridae virus is a respiratory syncytial virus.In some embodiments, the Pneumoviridae virus is human metapneumovirus.

In some embodiments, the present disclosure provides a compound of thedisclosure provided herein, or pharmaceutically acceptable salt thereof,for use in a manufacture of a medicament for treating a Paramyxoviridaevirus infection. Paramyxoviridae viruses include, but are not limited toNipah virus, Hendra virus, measles, mumps, and parainfluenza virus. Insome embodiments, the Paramyxoviridae virus is Nipah or parainfluenzavirus. In some embodiments, the Paramyxoviridae virus is Nipah. In someembodiments, the Paramyxoviridae virus is parainfluenza.

D. Additional Uses

In some embodiments, the present disclosure provides a method ofoptimizing a plasma or blood concentration of a compound of Formula II,or a pharmaceutically acceptable salt thereof, in a human in needthereof:

the method comprising administering to the human an antiviral compound,wherein the human has not been administered chloroquine, or an analog orsalt thereof, the antiviral compound is converted to the compound ofFormula II upon administration to the human, and the plasma or bloodconcentration of the compound of Formula II is optimized in the absenceof chloroquine, or an analog or salt thereof. In some embodiments, thehuman has not been administered chloroquine, or an analog or saltthereof, within 1 day of administering to the human an antiviralcompound. In some embodiments, the human has not been administeredchloroquine, or an analog or salt thereof, within 10 days ofadministering to the human an antiviral compound.

In some embodiments, the human has not been administered chloroquine, oran analog or salt thereof, within 30 mins, 1 hour, 2 hours, 3 hours, 4hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 20hours, or 24 hours of administering to the human an antiviral compound.In some embodiments, the human has not been administered chloroquine, oran analog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days,6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days,210 days, 240 days, 270 days, 300 days, 330 days, or 365 days, ofadministering to the human an antiviral compound. In some embodiments,the human has a plasma or blood concentration of the chloroquine, or ananalog or salt thereof, of less than 50 ng/mL, such as less than 45ng/mL, 40 ng/mL, 35 ng/mL, 30 ng/mL, 25 ng/mL, 20 ng/mL, 15 ng/mL, 10ng/mL, or 5 ng/mL, at the time a first dose of the antiviral compound isadministered to the human. In some embodiments, the human has a plasmaor blood concentration of the chloroquine, or an analog or salt thereof,of less than 50 ng/mL, at the time a first dose of the antiviralcompound is administered to the human.

In some embodiments, the antiviral compound is a compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof. In some embodiments, the plasma or blood concentration of thecompound of Formula II in the human is higher than a secondconcentration of a compound of Formula II in a reference human treatedwith chloroquine, or an analog or salt thereof, and the antiviralcompound. In some embodiments, the plasma or blood concentration of thecompound of Formula II in the human is from about 1.1 times to about 10times higher, such as from about 1.2 times to about 5 times, from about1.3 times to about 5 times, from about 1.2 times to about 4 times, fromabout 1.3 times to about 4 times, from about 1.2 times to about 3 times,from about 1.3 times to about 3 times, from about 1.2 times to about 2times, or from about 1.3 times to about 2 times, higher than a secondconcentration of the compound in a reference human treated withchloroquine, or an analog or salt thereof, and the antiviral compound.In some embodiments, the plasma or blood concentration of the compoundof Formula II in the human is at least 1.1 times higher, such as atleast 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times,1.8 times, 1.9 times, 2 times, 2.1 times, 2.2 times, 2.3 times, 2.4times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3 times,3.2 times, 3.5 times, 3.6 times, 3.8 times, 4 times, 4.2 times, 4.4times, 4.6 times, 4.8 times, 5 times, 6 times, 7 times, 8 times, 9times, or 10 times higher than a second concentration of the compound ina reference human treated with chloroquine, or an analog or saltthereof, and the antiviral compound.

In some embodiments, the present disclosure provides a method ofoptimizing a plasma or blood concentration of a compound of Formula II,or a pharmaceutically acceptable salt thereof, in a human in needthereof, comprises: (a) administering to the human a compound of FormulaI, Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof (b) measuring the plasma or blood concentration of the compoundof Formula II in the human; and (c) adjusting any remaining doses of thecompound of Formula I, Formula Ia, or Formula Ib, to optimize the plasmaor blood concentration of the compound of Formula II in the human. Insome embodiments, the method comprises administering to the human adaily dose. In some embodiments, the method comprises administering tothe human 10 daily doses.

In some embodiments, the plasma or blood concentration of the compoundof Formula II in the human is from about 1.1 times to about 10 timeshigher, such as from about 1.2 times to about 5 times, from about 1.3times to about 5 times, from about 1.2 times to about 4 times, fromabout 1.3 times to about 4 times, from about 1.2 times to about 3 times,from about 1.3 times to about 3 times, from about 1.2 times to about 2times, or from about 1.3 times to about 2 times, higher than a secondconcentration of the compound in a reference human treated withchloroquine, or an analog or salt thereof, and a compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof. In some embodiments, the plasma or blood concentration of thecompound of Formula II in the human is at least 1.1 times higher, suchas at least 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7times, 1.8 times, 1.9 times, 2 times, 2.1 times, 2.2 times, 2.3 times,2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3times, 3.2 times, 3.5 times, 3.6 times, 3.8 times, 4 times, 4.2 times,4.4 times, 4.6 times, 4.8 times, 5 times, 6 times, 7 times, 8 times, 9times, or 10 times higher than a second concentration of the compound ina reference human treated with chloroquine, or an analog or saltthereof, and a compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method ofdetermining a delivery dose of a compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof, for treatinga viral infection in a human in need thereof, the method comprising: (a)providing an original dose of the compound of Formula I, Formula Ia, orFormula Ib, or a pharmaceutically acceptable salt thereof; (b)determining whether the human has been administered chloroquine, or ananalog or salt thereof; and (c1) if the human has been administeredchloroquine, or an analog or salt thereof, increasing the original doseof the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, to determine the deliverydose, or (c2) if the human has not been administered chloroquine, or ananalog or salt thereof, selecting the original dose of the compound ofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptablesalt thereof, as the delivery dose.

In some embodiments, the method of determining a delivery dose comprisesdetermining whether the human has been administered chloroquine, or ananalog thereof, within 1 day prior to the treatment of the viralinfection. In some embodiments, the method comprises determining whetherthe human has been administered chloroquine, or an analog thereof,within 10 days prior to the treatment of the viral infection. In someembodiments, determining whether the human has been administeredchloroquine, or an analog thereof, comprises self-reporting,interviewing the human, reviewing the human's medical records, ormeasuring the level of chloroquine, or an analog or salt thereof, in theplasma or blood in the human. In some embodiments, the human has notbeen administered chloroquine, or an analog or salt thereof, within 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300days, 330 days, or 365 days, of administering to the human an antiviralcompound.

In some embodiments, the human has not been administered chloroquine, oran analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours,4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20hours of receiving a first dose of the compound of Formula I, FormulaIa, or Formula Ib, or a pharmaceutically acceptable salt thereof.

In some embodiments, when the human has been administered chloroquine,or an analog or salt thereof, prior to treating the viral infection, themethod comprises increasing the original dose of the compound of FormulaI, Formula Ia, or Formula Ib, or pharmaceutically acceptable saltthereof, by from about 1.1 times to about 10 times higher, to determinethe delivery dose, or from about 1.2 times to about 5 times, from about1.3 times to about 5 times, from about 1.2 times to about 4 times, fromabout 1.3 times to about 4 times, from about 1.2 times to about 3 times,from about 1.3 times to about 3 times, from about 1.2 times to about 2times, or from about 1.3 times to about 2 times, higher to determine thedelivery dose. In some embodiments, when the human has been administeredchloroquine, or an analog or salt thereof, prior to treating the viralinfection, the method comprises increasing the original dose of thecompound of Formula I, Formula Ia, or Formula Ib, or pharmaceuticallyacceptable salt thereof, by at least 1.1 times higher to determine thedelivery dose, or at least 1.2 times, 1.3 times, 1.4 times, 1.5 times,1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.1 times, 2.2times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times,2.9 times, 3 times, 3.2 times, 3.5 times, 3.6 times, 3.8 times, 4 times,4.2 times, 4.4 times, 4.6 times, 4.8 times, 5 times, 6 times, 7 times, 8times, 9 times, or 10 times higher, to determine the delivery dose. Insome embodiments, the human has not been administered chloroquine, or ananalog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20hours of receiving a first dose of the compound of Formula I, FormulaIa, or Formula Ib, or a pharmaceutically acceptable salt thereof. Insome embodiments, the human has not been administered chloroquine, or ananalog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days,210 days, 240 days, 270 days, 300 days, 330 days, or 365 days, ofadministering to the human an antiviral compound.

In some embodiments, the present disclosure provides a method of forminga compound of Formula II in a human in need thereof, comprisingadministering to the human a therapeutically effective amount of acompound of Formula Ia, and instructing the human not to takechloroquine, or an analog or salt thereof, wherein the compound ofFormula Ia is metabolized to the compound of Formula II in the absenceof chloroquine, or an analog or salt thereof. In some embodiments, thehuman has not been administered chloroquine, or an analog or saltthereof, within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours,6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours of receivinga first dose of the compound of Formula Ia. In some embodiments, thehuman has not been administered chloroquine, or an analog or saltthereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240days, 270 days, 300 days, 330 days, or 365 days, of administering thecompound of Formula Ia. In some embodiments, after instructing the humannot to take chloroquine, or an analog or salt thereof, the human waitsat least 1 day before administering the compound of Formula Ia.

In some embodiments, the present disclosure provides a method ofreducing the risk of decreased efficacy of the compound of Formula Ia,or a pharmaceutically acceptable salt thereof, in a human suffering froma viral infection, comprises: (a) determining if the human has takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof, (b) instructing the human not to take chloroquine, or an analogor salt thereof, while being treated with the compound of Formula Ia, ora pharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby reducing the risk of decreased efficacy of thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof.In some embodiments, the human has not been administered chloroquine, oran analog or salt thereof, within 30 minutes, 1 hour, 2 hours, 3 hours,4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20hours of receiving a first dose of the compound of Formula I, FormulaIa, or Formula Ib, or a pharmaceutically acceptable salt thereof. Insome embodiments, the human has not been administered chloroquine, or ananalog or salt thereof, within 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days,210 days, 240 days, 270 days, 300 days, 330 days, or 365 days, ofadministering the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof. In some embodiments, if the human is determinedto have taken chloroquine, or an analog or salt thereof, prior toadministration of the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, the human waits at least 1 day beforeadministering the compound of Formula Ia, or pharmaceutically acceptablesalt thereof.

For the methods of the present disclosure requiring instructing thehuman not to take chloroquine, or an analog or salt thereof, while beingtreated with the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, any number of actions alone or in combinationcan be taken in the event that the human is administered chloroquine, oran analog or salt thereof, after receiving the instructions and afterreceiving the compound of Formula Ia, or a pharmaceutically acceptablesalt thereof. In some embodiments, the human stops taking chloroquine,or an analog or salt thereof. In some embodiments, the human waits afterthe last dose of chloroquine, or an analog or salt thereof, for at least30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8hours, 10 hours, 12 hours, 16 hours, or 20 hours before receiving afirst dose of the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof. In some embodiments, the humanwaits after the last dose of chloroquine, or an analog or salt thereof,for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days, 45 days, 60days, 75 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240days, 270 days, 300 days, 330 days, or 365 days before receiving a firstdose of the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof. In some embodiments, afterinstructing the human not to take chloroquine, or an analog or saltthereof, the human waits at least 1 day before administering thecompound of Formula Ia, or pharmaceutically acceptable salt thereof. Insome embodiments, the human takes an additional 1 dose, 2 doses, 3doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, or 10 dosesof the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, as compared to a referencehuman who has not been administered chloroquine, or an analog or saltthereof. In some embodiments, the human takes a higher dose of thecompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, as compared to a reference human who has notbeen administered chloroquine, or an analog or salt thereof, or at least1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7times, 1.8 times, 1.9 times, 2 times, 2.1 times, 2.2 times, 2.3 times,2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3times, 3.2 times, 3.5 times, 3.6 times, 3.8 times, 4 times, 4.2 times,4.4 times, 4.6 times, 4.8 times, 5 times, 6 times, 7 times, 8 times, 9times, or 10 times higher dose of the compound of Formula I, Formula Ia,or Formula Ib, or a pharmaceutically acceptable salt thereof, ascompared to a reference human who has not been administered chloroquine,or an analog or salt thereof.

In some embodiments, the present disclosure provides a method ofpreventing a contraindication in a human suffering from a viralinfection, the method comprising: (a) determining if the human has takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof, (b) instructing the human not to take chloroquine, or an analogor salt thereof, while being treated with the compound of Formula Ia, ora pharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby preventing a contraindication in the human. Insome embodiments, if the human is determined to have taken chloroquine,or an analog or salt thereof, prior to administration of the compound ofFormula Ia, or a pharmaceutically acceptable salt thereof, the humanwaits at least 1 day before administering the compound of Formula Ia, orpharmaceutically acceptable salt thereof.

In some embodiments, preventing a contraindication in the human is incomparison to a second human who has taken chloroquine, or an analog orsalt thereof, prior to the administration of the compound of Formula Ia,or pharmaceutically acceptable salt thereof, or who has not beeninstructed not to take chloroquine, or an analog or salt thereof. Insome embodiments, the second human who has taken chloroquine, or ananalog or salt thereof, prior to the administration of the compound ofFormula Ia, or pharmaceutically acceptable salt thereof, is more likelythan the human to have a contraindication after administration of thecompound of Formula Ia or pharmaceutically acceptable salt thereof. Insome embodiments, the second human who has not been instructed not totake chloroquine, or an analog or salt thereof, prior to theadministration of the compound of Formula Ia, or pharmaceuticallyacceptable salt thereof, is more likely than the human to have acontraindication after administration of the compound of Formula Ia orpharmaceutically acceptable salt thereof. In some embodiments, thesecond human is at least 1.1 times, such as 1.2 times, 1.3 times, 1.4times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times,2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7times, 2.8 times, 2.9 times, 3 times, 3.2 times, 3.5 times, 3.6 times,3.8 times, 4 times, 4.2 times, 4.4 times, 4.6 times, 4.8 times, 5 times,6 times, 7 times, 8 times, 9 times, or 10 times more likely than thehuman to have a contraindication after administration of the compound ofFormula Ia or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method ofmaintaining efficacy of a compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, in a human suffering from a viral infection,the method comprising: (a) determining if the human has takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof, (b) instructing the human not to take chloroquine, or an analogor salt thereof, while being treated with the compound of Formula Ia, ora pharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby maintaining efficacy of the compound of FormulaIa, or a pharmaceutically acceptable salt thereof. In some embodiments,maintaining efficacy comprises maintaining a sufficient plasma or bloodconcentration of the compound of Formula II in the human afteradministration as compared to a second human that has not takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof. In some embodiments, the plasma or blood concentration of thecompound of Formula II in the human after administration is from about50% to about 100% of a second plasma or blood concentration of thecompound of Formula II in a second human that has not taken chloroquine,or an analog or salt thereof, prior to administration of the compound ofFormula Ia, or a pharmaceutically acceptable salt thereof, or from about60% to about 100%, from about 70% to about 100%, from about 80% to about100%, or from about 90% to about 100%, of a second plasma or bloodconcentration of the compound of Formula II in a second human that hasnot taken chloroquine, or an analog or salt thereof, prior toadministration of the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof. In some embodiments, if the human is determinedto have taken chloroquine, or an analog or salt thereof, prior toadministration of the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, the human waits at least 1 day beforeadministering the compound of Formula Ia, or pharmaceutically acceptablesalt thereof.

In some embodiments, the present disclosure provides a method ofreducing the risk of a reduced plasma concentration of a compound ofFormula II, in a human suffering from a viral infection, the methodcomprising: (a) determining if the human has taken chloroquine, or ananalog or salt thereof, prior to administration of the compound ofFormula Ia, or a pharmaceutically acceptable salt thereof, (b)instructing the human not to take chloroquine, or an analog or saltthereof, while being treated with the compound aof Formula Ia, or apharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby reducing the risk of a reduced plasmaconcentration of the compound of Formula II. In some embodiments, if thehuman is determined to have taken chloroquine, or an analog or saltthereof, prior to administration of the compound of Formula Ia, or apharmaceutically acceptable salt thereof, the human waits at least 1 daybefore administering the compound of Formula Ia, or pharmaceuticallyacceptable salt thereof.

In some embodiments, reducing the risk of a reduced plasma concentrationof a compound of Formula II comprises maintaining a sufficientconcentration of the compound of Formula II in the plasma of the humanafter administration of the compound of Formula Ia, or apharmaceutically acceptable salt thereof, as compared to a second humanthat has not taken chloroquine, or an analog or salt thereof, prior toadministration of the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the plasma concentrationof the compound of Formula II in the human after administration is fromabout 50% to about 100% of a second concentration of the compound ofFormula II in a second human that has not taken chloroquine, or ananalog or salt thereof, prior to administration of the compound ofFormula Ia, or a pharmaceutically acceptable salt thereof, or from about60% to about 100%, from about 70% to about 100%, from about 80% to about100%, or from about 90% to about 100%, of a second concentration of thecompound of Formula II in a second human that has not taken chloroquine,or an analog or salt thereof, prior to administration of the compound ofFormula Ia, or a pharmaceutically acceptable salt thereof.

For the methods of the present disclosure requiring determining if thehuman has taken chloroquine, or an analog or salt thereof, prior toadministration of the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof, the determining can be performed by anysuitable means. For example, non-limiting techniques includeself-reporting, interviewing the human, reviewing the human's medicalrecords, or measuring the level of chloroquine, or an analog or saltthereof, in the plasma or blood in the human. In some embodiments, thedetermining includes measuring the level of chloroquine, or ametabolite, analog or salt thereof, in the plasma or blood in the human.

IV. Kits

In some embodiments, the present disclosure provides the use of a kitcomprising a compound or composition disclosed herein. In someembodiments, the kit further comprises a label and/or instructions forusing the compound or pharmaceutical composition in the method of thepresent disclosure. For instance, in some embodiments, the kit comprisesinstructing the human not to take chloroquine, or an analog or saltthereof, during the treatment of the viral infection.

In some embodiments, the kit comprises instructing the human to waitafter taking chloroquine, or an analog or salt thereof, at least 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours,10 hours, 12 hours, 16 hours, or 20 hours before administering thecompound of Formula I, Formula Ia or Formula Ib, or pharmaceuticallyacceptable salt thereof. In some embodiments, the kit comprisesinstructing the human to wait after taking chloroquine, or an analog orsalt thereof, such as at least 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30days, 45 days, 60 days, 75 days, 90 days, 120 days, 150 days, 180 days,210 days, 240 days, 270 days, 300 days, 330 days, or 365 days aftertaking chloroquine, or an analog or salt thereof, before administeringthe compound of Formula I, Formula Ia or Formula Ib, or pharmaceuticallyacceptable salt thereof. In some embodiments, the kit comprisesinstructing the human to wait at least 1 day after taking chloroquine,or an analog or salt thereof, before administering the compound ofFormula I, Formula Ia or Formula Ib, or pharmaceutically acceptable saltthereof. In some embodiments, the kit comprises instructing the human towait at least 10 days after taking chloroquine, or an analog or saltthereof, before administering the compound of Formula I, Formula Ia orFormula Ib, or pharmaceutically acceptable salt thereof. In someembodiments, the kit comprises instructing the human to wait at least 14days after taking chloroquine, or an analog or salt thereof, beforeadministering the compound of Formula I, Formula Ia or Formula Ib, orpharmaceutically acceptable salt thereof. In some embodiments, the kitcomprises instructing the human to wait at least 21 days after takingchloroquine, or an analog or salt thereof, before administering thecompound of Formula I, Formula Ia or Formula Ib, or pharmaceuticallyacceptable salt thereof.

In some embodiments, the kit comprises instructing the human to waitafter taking chloroquine, or an analog or salt thereof, at least 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours,10 hours, 12 hours, 16 hours, or 20 hours before administering thecompound of Formula Ia, or pharmaceutically acceptable salt thereof. Insome embodiments, the kit comprises instructing the human to wait aftertaking chloroquine, or an analog or salt thereof, such as at least 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 14 days, 21 days, 28 days, 30 days, 45 days, 60 days, 75 days, 90days, 120 days, 150 days, 180 days, 210 days, 240 days, 270 days, 300days, 330 days, or 365 days after taking chloroquine, or an analog orsalt thereof, before administering the compound of Formula Ia, orpharmaceutically acceptable salt thereof. In some embodiments, the kitcomprises instructing the human to wait at least 10 days after takingchloroquine, or an analog or salt thereof, before administering thecompound of Formula Ia, or pharmaceutically acceptable salt thereof. Insome embodiments, the kit comprises instructing the human to wait atleast 14 days after taking chloroquine, or an analog or salt thereof,before administering the compound of Formula Ia, or pharmaceuticallyacceptable salt thereof. In some embodiments, the kit comprisesinstructing the human to wait at least 21 days after taking chloroquine,or an analog or salt thereof, before administering the compound ofFormula Ia, or pharmaceutically acceptable salt thereof.

In some embodiments, the kit further comprises a nebulizer. Any suitablenebulizer may be used. In some embodiments, the nebulizer is a glassnebulizer. In some embodiments, the nebulizer is a hand bulb nebulizer.In some embodiments, the nebulizer is a jet nebulizer or a vibratingmesh nebulizer. In some embodiments, the nebulizer is a jet nebulizer(e.g. VixOne™ AeroEclipse®, Pari LC® Plus). In some examples thenebulizer is a vibrating mesh nebulizer (e.g. eFlow® rapid). In someembodiments, the nebulizer is a ultrasonic nebulizer. In someembodiments, the nebulizer is an adaptive aerosol delivery nebulizer. Insome embodiments, the nebulizer is a metered dose inhaler (e.g. ametered dose liquid inhaler).

V. EXAMPLES Example 1. Chloroquine Effect on Compound of Formula Ia inCells

Antiviral potency of the compound of Formula Ia against respiratorysyncytial virus (RSV) was determined in HEp2 cells in the followingmanner. HEp2 cells (3×103/well) were suspended in DMEM medium+GlutaMAX(supplemented with 10% FBS and 1% Penicillin/Streptomycin) and seededinto 96 well plates. After a 4-hour incubation at 37° C.+5% CO₂,three-fold serial dilutions of the compound (final RDV concentration of9.28 nM to 2000 nM) were added to each well using an HP D300e digitaldispenser. To determine the effect of chloroquine (CQ) on Formula Iaantiviral activity, the Formula Ia dilution series was additionallyspiked with DMSO or 4× increasing concentrations of CQ (finalconcentrations: 10 nM, 40 nM, 160 nM, 640 nM, and 2560 nM). The cellswere then infected with RSV A2 virus diluted in DMEM medium+GlutaMAX atan MOI=4 and incubated for 4 days at 37° C. and 5% CO₂. The final volumein each well was 200 μL. Uninfected and untreated wells were included ascontrols for 100% cell viability. Following the incubation, 100 μL ofculture supernatant was removed from each well and replaced with 100 μLof CellTiter-Glo reagent (Promega). The plates were then rocked for 2minutes followed by a 10-minute incubation at 25° C. Cell viability wasthen assessed by measuring luminescence signal using and Envision platereader. Values were normalized to the uninfected and infected DMSOcontrols (as 100% and 0% infection, respectively) and data was fit usingnon-linear regression analysis with the XLfit software. EC₅₀ values weredetermined as the point the non-linear regression curve of 50%infection. The compiled data was generated using three biologicalreplicates each containing technical duplicates for each CQconcentration.

The effect of the combination of the compound of Formula Ia andconcentrations of chloroquine (CQ) on RSV replication in HEp2 cells weremeasured. Results show that CQ antagonizes the anti-RSV activity of thecompound of Formula Iain a dose-dependent manner as demonstrated byhigher Formula Ia EC₅₀ values with increasing concentrations of CQ(Table 1).

TABLE 1 Effect of Chloroquine on Anti-RSV Activity of Formula Ia in HEp2Cells Chloroquine Formula Ia RSV Formula Ia RSV (nM) EC₅₀ (nM) EC₅₀ foldchange P value 0  49.5 ± 13.1 1 — 10  58.4 ± 12.8 1.19 ± 0.10 0.075 40 72.1 ± 24.8 1.45 ± 0.19 0.052 160  99.6 ± 30.3 2.02 ± 0.17 0.0088 640138.3 ± 33.8 2.86 ± 0.50 0.023 2560 209.0 ± 18.2 4.43 ± 1.13 0.034

Example 2: Metabolism Data

A549-hACE2 and NHBE cells were seeded in 6-well plates at 4×10⁵ and2.5×10⁵ cells/well, respectively. HEp-2 cells were seeded in 12-wellplates at 2.5×10⁵ cells/well. Twenty-four hours later, cell culturemedium was replaced with medium containing 1 μM Formula Ia alone, or incombination with 1 or 10 μM of either CQ or HCQ, and incubated at 37° C.At 2, 8, 24 and 48 h post drug addition, cells were washed 3 times withice-cold tris-buffered saline, scraped into 0.5 mL ice-cold 70% methanoland stored at −80° C. Extracts were centrifuged at 15,000 g for 15minutes and supernatants were transferred to clean tubes for evaporationin a miVac Duo concentrator (Genevac). Dried samples were reconstitutedin mobile phase A containing 3 mM ammonium formate (pH 5) with 10 mMdimethylhexylamine (DMHA) in water for analysis by LC-MS/MS, using amulti-stage linear gradient from 10% to 50% acetonitrile in mobile phaseA at a flow rate of 360 μL/min. Analytes were separated using a 50×2 mm,2.5 μm Luna C18(2) HST column (Phenomenex) connected to an LC-20ADXR(Shimadzu) ternary pump system and an HTS PAL autosampler (LEAPTechnologies). Detection was performed on a Qtrap (6500+AB Sciex) massspectrometer operating in positive ion and multiple reaction monitoringmodes. Analytes were quantified using a 7-point standard curve rangingfrom 0.624 to 160 pmol per million cells prepared in extracts fromuntreated cells. For normalization by cell number, multiple untreatedculture wells were counted at each timepoint.

The metabolism of the compound of Formula Ia to the active triphosphatespecies (Formula Ia-TP) species was evaluated in A549-hACE2, NHBE, andHEp-2 cell cultures following incubation with the compound of Formula Iaalone and when combined with CQ or HCQ. The concentrations of CQ and HCQused in these in vitro assays correspond to systemic and lung exposuresthat result from doses recommended under the former EUA guidance forCOVID-19. The average systemic exposures range from 610-760 nM for CQand approximately 1.7 μM for HCQ, which can achieve lung concentrationsin excess of 20 μM for either drug {Salman 2017, Zhao 2014}. InA549-hACE2 cells, co-incubation of the compound of Formula Ia and 1 μMCQ or HCQ did not significantly reduce Formula Ia-TP levels compared tothe Formula Ia-TP in the absence of CQ or HCQ; however, incubation at 10μM of either CQ or HCQ did significantly lower the production of FormulaIa-TP (Table 2; FIG. 1). While Formula Ia-TP levels trended lower inNHBE cultures treated with either concentration of CQ or 1 μM HCQ, thesedifferences were not statistically significant. Conversely, treatment ofNHBE cultures with 10 μM HCQ significantly reduced Formula Ia-TP levels(Table 3; FIG. 2). In HEp-2 cervical carcinoma cells, treatment with CQor HCQ at either 1 or 10 μM showed a dose-dependent reduction information of intracellular Formula Ia-TP (Table 4; FIG. 3). SignificantCQ or HCQ antagonism of Formula Ia-TP formation in Hep-2 cells wasobserved at 8 h post treatment and persisted for 48 h. The observedreductions in Formula Ia-TP in the presence of CQ or HCQ indicates apotential antagonistic effect on the compound of Formula Ia metabolismto its active triphosphate.

TABLE 2 Effect of CQ or HCQ on RDV-TP Formation in A549-hACE2 Cells MeanRDV-TP (pmol/million cells)^(a) 1 μM 1 μM 1 μM 1 μM Formula Formula IaFormula Ia Formula Ia Ia Treatment 1 μM + + + + time (h) Formula Ia 1 μMCQ 10 μM CQ 1 μM HCQ 10 μM HCQ  2 3.6 ± 0.2 2.4 ± 0.1 0.7 ± 0.1 2.8 ±0.3 1.0 ± 0.1  8 11.4 ± 0.8  10.0 ± 0.3  2.5 ± 0.1 10.3 ± 1.2  2.2 ± 0.324 6.8 ± 1.3 5.8 ± 1.2 1.7 ± 0.4 7.0 ± 2.0 2.2 ± 0.6 48 3.0 ± 0.5 2.9 ±0.6 1.8 ± 0.4 2.8 ± 0.3 1.8 ± 0.4 Average 6.5 ± 0.8 5.6 ± 0.8 1.8 ± 0.36.2 ± 1.3 2.0 ± 0.4 Formula Ia-TP concentration (pmol/million cells)^(b)P value^(c) NA 0.8497 0.0030 0.9960 0.0041 ^(a)Values are mean ± SEM ofduplicate samples collected at each timepoint from two separateexperiments. ^(b)Average Formula Ia-TP concentration was determinedusing GraphPad Prism 8.1.2 from the total area under the curve fromFormula Ia-TP concentrations detected by LC-MS at 0, 2, 8, 24, and 48 h;and divided by the total time of the assay (48 h). ^(c)P value isdetermined using one-way ANOVA with Dunnett's multiple comparisonanalysis of Formula Ia + DMSO compared to various concentrations of CQor HCQ using GraphPad Prism 8.1.2.

TABLE 3 Effect of CQ or HCQ on RDV-TP Formation in NHBE Cultures MeanRDV-TP (pmol/million cells)^(a) 1 μM 1 μM 1 μM 1 μM Formula Formula IaFormula Ia Formula Ia Ia Treatment 1 μM + + + + time (h) Formula Ia 1 μMCQ 10 μM CQ 1 μM HCQ 10 μM HCQ  2 4.4 ± 0.5 2.2 ± 0.2 1.8 ± 0.5 2.2 ±0.2 1.1 ± 0.5  8 19.4 ± 3.8  12.1 ± 2.8  12.3 ± 4.6  11.1 ± 1.8  9.9 ±1.4 24 16.7 ± 1.0  12.9 ± 1.2  9.7 ± 0.6 10.8 ± 1.2  9.2 ± 1.2 48 14.2 ±0.6  14.7 ± 0.5  13.0 ± 1.0  13.6 ± 0.5  10.5 ± 0.6  Average 15.3 ± 1.5 12.0 ± 1.2  10.2 ± 1.8  10.6 ± 1.0  8.8 ± 0.9 Formula Ia-TPconcentration (pmol/million cells)^(b) P value^(c) NA 0.2724 0.05070.0753 0.0112 ^(a)Values are mean ± SEM of duplicate samples collectedat each timepoint from two separate experiments. ^(b)Average Formula Ia-concentration was determined using GraphPad Prism 8.1.2 from the totalarea under the curve from Formula Ia-TP concentrations detected by LC-MSat 0, 2, 8, 24, and 48 h; and divided by the total time of the assay (48h). ^(c)P value is determined using one-way ANOVA with Dunnett'smultiple comparison analysis of Formula Ia + DMSO compared to variousconcentrations of CQ or HCQ using GraphPad Prism 8.1.2.

TABLE 4 Effect of CQ or HCQ on RDV-TP Formation in HEp-2 cells MeanRDV-TP (pmol/million cells)^(a) 1 μM 1 μM 1 μM 1 μM Formula Formula IaFormula Ia Formula Ia Ia Treatment 1 μM + + + + time (h) Formula Ia 1 μMCQ 10 μM CQ 1 μM HCQ 10 μM HCQ  2 BLQ BLQ BLQ BLQ BLQ  8 22.8 ± 1.4 7.7± 0.3 3.0 ± 0.5 5.8 ± 1.2 0.4 ± 0.3 24 40.8 ± 5.6 15.9 ± 2.0  6.2 ± 1.015.0 ± 3.2  3.9 ± 0.8 48 45.9 ± 5.6 20.7 ± 3.2  10.2 ± 2.0  20.0 ± 2.5 7.8 ± 0.6 Average 33.7 ± 4.4 13.6 ± 2.0  5.8 ± 1.2 12.6 ± 2.3  3.7 ± 0.6Formula Ia-TP concentration (pmol/million cells)^(b) P value^(c) NA0.0002 <0.0001 <0.0001 <0.0001 ^(a)Values are mean ± SEM of duplicatesamples collected at each timepoint from two separate experiments.^(b)Average Formula Ia-TP concentration was determined using GraphPadPrism 8.1.2 from the total area under the curve from Formula Ia-TPconcentrations detected by LC-MS at 0, 2, 8, 24, and 48 h; and dividedby the total time of the assay (48 h). ^(c)P value is determined usingone-way ANOVA with Dunnett's multiple comparison analysis of FormulaIa + DMSO compared to various concentrations of CQ or HCQ using GraphPadPrism 8.1.2.

Example 3. SARS-CoV-2 Antiviral Data

The anti-SARS-CoV-2 activities of the compound of Formula Ia and eitherCQ or HCQ were evaluated in A549-hACE2 transformed airway epithelialcells. The compound of Formula Ia, CQ, and HCQ individually exhibitpotent in vitro antiviral activities against SARS-CoV-2, with EC₅₀values of approximately 59.5 nM, 451 nM, and 365 nM, respectively (Table5). The compound of Formula Ia EC₅₀ values were not observably differentwhen combined with CQ or HCQ at concentrations up to 2.5 μM (Table 5);however, the overall Nluc signal in the assay decreased in the presenceof CQ or HCQ in a dose-dependent manner (FIG. 4A and FIG. 4B). As shownin FIG. 4A, the Nluc signal at 0 μM Formula Ia (DMSO)+CQ corresponds tothe Nluc signal at the specific CQ concentration in that treatmentcondition. The baseline Nluc signal of each Formula Ia titration curveis lowered to levels corresponding to the CQ concentration in thattreatment condition. Similar effects are observed in the HCQ-treatmentconditions FIG. 4B). At 10 μM of either CQ or HCQ alone, the Nluc signalwas fully suppressed, indicating a complete inhibition of SARS-CoV-2replication by either CQ or HCQ alone. Due to the potent antiviralactivity of CQ and HCQ at the 10 μM concentration, a standard EC₅₀ valuecomparison is unable to reveal the potential decrease in Formula Iaactivity against SARS-CoV-2 when combined with CQ or HCQ. Cytotoxicitywas not observed at Formula Ia and HCQ combination concentrationsanalyzed (data not shown).

TABLE 5 SARS-CoV-2 Nluc EC50 values of RDV + CQ or HCQ in A549-hACE2cells Treatment EC₅₀ (nM)^(b) Formula Ia +DMSO 59.5 CQ +DMSO 451 HCQ+DMSO 365 Formula Ia + 10 nm CQ 52.0 Formula Ia + 40 nm CQ 52.4 FormulaIa + 160 nm CQ 52.2 Formula Ia + 640 nm CQ 46.0 Formula Ia + 2500 nm CQ39.8 Formula Ia + 10000 nm CQ ND^(c) Formula Ia + 10 nm HCQ 63.6 FormulaIa + 40 nm HCQ 50.7 Formula Ia + 160 nm HCQ 60.0 Formula Ia + 640 nm HCQ56.2 Formula Ia + 2500 nm HCQ 63.0 Formula Ia + 10000 nm HCQ ND^(c)^(a)n = 1 ^(b)EC₅₀ values were defined in GraphPad Prism 8.1.2 as theconcentration at which there was a 50% decrease in the Nluc counts persecond (CPS) relative to DMSO vehicle alone (0% virus inhibition) anduninfected control culture (100% virus inhibition). ^(c)ND denotes whereEC₅₀ values could not be calculated due to complete inhibition of Nlucsignal by CQ or HCQ.

Although the foregoing disclosure has been described in some detail byway of illustration and Example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference. Where a conflictexists between the instant application and a reference provided herein,the instant application shall dominate.

1. A method of treating a viral infection in a human in need thereof,the method comprising administering to the human a therapeuticallyeffective amount of a compound of Formula I, Formula Ia, or Formula Ib,or a pharmaceutically acceptable salt thereof:

wherein the human is not being treated with chloroquine, or an analog orsalt thereof, thereby treating the viral infection.
 2. The method ofclaim 1, wherein the human has not been administered chloroquine, or ananalog or salt thereof, within 1 day of receiving a first dose of thecompound of Formula I, Formula Ia, or Formula Ib, or pharmaceuticallyacceptable salt thereof.
 3. The method of claim 2, wherein the human hasnot been administered chloroquine, or an analog or salt thereof, within10 days of receiving the first dose of the compound of Formula I,Formula Ia, or Formula Ib, or pharmaceutically acceptable salt thereof.4.-5. (canceled)
 6. The method of claim 1, further comprisinginstructing the human not to take chloroquine, or an analog or saltthereof, during the treatment of the viral infection.
 7. (canceled) 8.The method of claim 1, wherein the human is not administeredchloroquine, or an analog or salt thereof, during the treatment of theviral infection.
 9. The method of claim 1, wherein the human has aplasma or blood concentration of the chloroquine, or an analog or saltthereof, of less than 50 ng/mL, at the time a first dose of the compoundof Formula I, Formula Ia, or Formula Ib, or pharmaceutically acceptablesalt thereof, is administered to the human.
 10. The method of claim 1,wherein the chloroquine, or an analog or salt thereof, is chloroquine,desethylchloroquine, hydroxychloroquine, desethylhydroxychloroquine, orbidesethylhydroxychloroquine, or a pharmaceutically acceptable saltthereof.
 11. The method of claim 10, wherein the chloroquine, or ananalog or salt thereof, is chloroquine, or a pharmaceutically acceptablesalt thereof.
 12. (canceled)
 13. The method of claim 10, wherein thechloroquine, or an analog or salt thereof, is hydroxychloroquine, or apharmaceutically acceptable salt thereof.
 14. (canceled)
 15. The methodof claim 1, comprising administering to the human the therapeuticallyeffective amount of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof:


16. The method of claim 1, comprising administering to the human thetherapeutically effective amount of the compound of Formula Ia, or apharmaceutically acceptable salt thereof:


17. The method of claim 1, comprising administering to the human thetherapeutically effective amount of the compound of Formula Ia:


18. (canceled)
 19. The method of claim 1, wherein the compound ofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptablesalt thereof, is administered intravenously.
 20. (canceled)
 21. Themethod of claim 1, wherein the human weighs at least 40 kg, and thecompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, is administered intravenously in the first doseof 200 mg on day 1, and administered intravenously in a second dose of100 mg on each of the following 4 days.
 22. The method of claim 21,wherein the second dose of 100 mg is administered for an additional 1 to5 days.
 23. (canceled)
 24. The method of claim 1, wherein the humanweighs from 3.5 kg to less than 40 kg, and the compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof, is administered intravenously in the first dose of 5 mg/kg onday 1, and administered intravenously in a second dose of 2.5 mg/kg oneach of the following 4 days. 25.-27. (canceled)
 28. The method of claim1, wherein the viral infection is caused by an Arenaviridae virus. 29.(canceled)
 30. The method of claim 1, wherein the viral infection iscaused by a Coronaviridae virus.
 31. The method of claim 30, wherein theCoronaviridae virus is SARS virus, SARS-CoV-2 virus, MERS virus, 229Evirus, NL63 virus, OC43 virus, or HKU1 virus.
 32. (canceled)
 33. Themethod of claim 30, wherein the Coronaviridae virus is SARS-CoV-2. 34.The method of claim 30, wherein the viral infection is caused by a virushaving at least 70% sequence homology to a viral polymerase selectedfrom the group consisting of SARS-CoV polymerase, SARS-CoV-2 polymerase,and MERS polymerase. 35.-37. (canceled)
 38. The method of claim 1,wherein the viral infection is caused by a Filoviridae virus.
 39. Themethod of claim 38, wherein the Filoviridae virus is Ebola or Marburg.40. The method of claim 1, wherein the viral infection is caused by aFlaviviridae virus. 41.-42. (canceled)
 43. The method of claim 1,wherein the viral infection is caused by a Pneumoviridae virus.
 44. Themethod of claim 43, wherein the Pneumoviridae virus is respiratorysyncytial virus or human metapneumovirus.
 45. (canceled)
 46. The methodof claim 1, wherein the viral infection is caused by a Paramyxoviridaevirus.
 47. The method of claim 46, wherein the Paramyxoviridae virus isNipah or parainfluenza virus.
 48. A method of optimizing a plasma orblood concentration of a compound of Formula II, or a pharmaceuticallyacceptable salt thereof, in a human in need thereof:

the method comprising administering to the human an antiviral compound,wherein the human has not been administered chloroquine, or an analog orsalt thereof, the antiviral compound is converted to the compound ofFormula II upon administration to the human, and the plasma or bloodconcentration of the compound of Formula II is optimized in the absenceof chloroquine, or an analog or salt thereof.
 49. The method of claim48, wherein the human has not been administered chloroquine, or ananalog thereof, within 1 day prior to the treatment of the viralinfection.
 50. The method of claim 48, wherein the human has not beenadministered chloroquine, or an analog thereof, within 10 days prior tothe treatment of the viral infection.
 51. The method of claim 48,wherein the human has a plasma or blood concentration of thechloroquine, or an analog or salt thereof, of less than 50 ng/mL, at thetime a first dose of the antiviral compound is administered to thehuman.
 52. The method of claim 48, wherein the plasma or bloodconcentration of the compound of Formula II in the human is higher thana second concentration of a compound of Formula II in a reference humantreated with chloroquine, or an analog or salt thereof.
 53. The methodof claim 48, wherein the antiviral compound is a compound of Formula I,Formula Ia, or Formula Ib, or a pharmaceutically acceptable saltthereof.
 54. A method of optimizing a plasma or blood concentration of acompound of Formula II, or a pharmaceutically acceptable salt thereof,in a human in need thereof:

the method comprising: (a) administering to the human a compound ofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptablesalt thereof:

(b) measuring the plasma or blood concentration of the compound ofFormula II in the human; and (c) adjusting any remaining doses of thecompound of Formula I, Formula Ia, or Formula Ib, to optimize the plasmaor blood concentration of the compound of Formula II in the human.55.-56. (canceled)
 57. A method of determining a delivery dose of acompound of Formula I, Formula Ia, or Formula Ib, or a pharmaceuticallyacceptable salt thereof, for treating a viral infection in a human inneed thereof,

the method comprising: (a) providing an original dose of the compound ofFormula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptablesalt thereof; (b) determining whether the human has been administeredchloroquine, or an analog or salt thereof; and (c1) if the human hasbeen administered chloroquine, or an analog or salt thereof, increasingthe original dose of the compound of Formula I, Formula Ia, or FormulaIb, or a pharmaceutically acceptable salt thereof, to determine thedelivery dose, or (c2) if the human has not been administeredchloroquine, or an analog or salt thereof, selecting the original doseof the compound of Formula I, Formula Ia, or Formula Ib, or apharmaceutically acceptable salt thereof, as the delivery dose. 58.-59.(canceled)
 60. A method of forming a compound of Formula II in a humanin need thereof, comprising administering to the human a therapeuticallyeffective amount of a compound of Formula Ia, and instructing the humannot to take chloroquine, or an analog or salt thereof, wherein thecompound of Formula Ia is metabolized to the compound of Formula II inthe absence of chloroquine, or an analog or salt thereof, wherein thecompound of Formula II has the structure:

 and wherein the compound of Formula Ia has the structure:


61. (canceled)
 62. A method of reducing the risk of decreased efficacyof the compound of Formula Ia, or a pharmaceutically acceptable saltthereof, in a human suffering from a viral infection,

the method comprising: (a) determining if the human has takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof, (b) instructing the human not to take chloroquine, or an analogor salt thereof, while being treated with the compound of Formula Ia, ora pharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby reducing the risk of decreased efficacy of thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof.63. (canceled)
 64. A method of preventing a contraindication in a humansuffering from a viral infection, the method comprising: (a) determiningif the human has taken chloroquine, or an analog or salt thereof, priorto administration of the compound of Formula Ia, or a pharmaceuticallyacceptable salt thereof,

(b) instructing the human not to take chloroquine, or an analog or saltthereof, while being treated with the compound of Formula Ia, or apharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby preventing a contraindication in the human. 65.(canceled)
 66. A method of maintaining efficacy of a compound of FormulaIa, or a pharmaceutically acceptable salt thereof, in a human sufferingfrom a viral infection,

the method comprising: (a) determining if the human has takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof, (b) instructing the human not to take chloroquine, or an analogor salt thereof, while being treated with the compound of Formula Ia, ora pharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human, thereby maintaining efficacy of the compound of FormulaIa, or a pharmaceutically acceptable salt thereof.
 67. (canceled)
 68. Amethod of reducing the risk of a reduced plasma concentration of acompound of Formula II, in a human suffering from a viral infection,

the method comprising: (a) determining if the human has takenchloroquine, or an analog or salt thereof, prior to administration ofthe compound of Formula Ia, or a pharmaceutically acceptable saltthereof, (b) instructing the human not to take chloroquine, or an analogor salt thereof, while being treated with the compound of Formula Ia, ora pharmaceutically acceptable salt thereof, and (c) administering thecompound of Formula Ia, or a pharmaceutically acceptable salt thereof,to the human,

thereby reducing the risk of a reduced plasma concentration of thecompound of Formula II.
 69. (canceled)